The purpose of this project is to elucidate the principles of treatment of chronic pain syndromes, with particular attention to the drug treatment of pain caused by nerve injury. In a randomized, double-blind, crossover study in 24 patients with painful diabetic neuropathy, 54% of patients had moderate or better relief with transdermal clonidine patches (an alpha2-adrenergic agonist commonly used as an antihypertensive) compared to 33% with placebo. For the entire group, the result of the crossover trial did not attain statistical significance (p=0.11). Seven patients, however, have had consistent return of pain with clonidine patch removal, and repeated relief with clonidine rechallenge, and continue to achieve relief up to a year after treatment was begun. This suggests that clonidine may be a useful advance in treatment for a subset of patients with neuropathic pain. A study of additional patients has been initiated designed to identify features of clonidine responders. The study incorporates a number of novel features to increase the statistical power with which response of a subset of patients can be identified. Because of growing evidence from animal studies that neuropathic pain may be mediated by spinal cord neurons depolarized by NMDA channels, the NMDA antagonist ketamine is being studies in two conditions; chronic pain in patients with nerve damage or reflex sympathetic dystrophy, and normal volunteers with hyperalgesia of the skin briefly induced by intradermal injection of capsaicin.